CN116726004A - 盐酸阿比多尔在制备改善或治疗肝损伤和肝纤维化药物中的应用 - Google Patents
盐酸阿比多尔在制备改善或治疗肝损伤和肝纤维化药物中的应用 Download PDFInfo
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- CN116726004A CN116726004A CN202310809378.5A CN202310809378A CN116726004A CN 116726004 A CN116726004 A CN 116726004A CN 202310809378 A CN202310809378 A CN 202310809378A CN 116726004 A CN116726004 A CN 116726004A
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Abstract
本发明公开了盐酸阿比多尔在制备改善或治疗肝损伤和肝纤维化药物中的应用。盐酸阿比多尔能够显著降低BDL小鼠血清AST与ALT酶活力水平,改善BDL诱导的小鼠肝组织病理学改变。因此,盐酸阿比多尔能够用于制备改善或治疗肝损伤和肝纤维化疾病的药物,所述肝纤维化疾病包括但不限于急慢性肝炎、肝硬化、脂肪肝。
Description
技术领域
本发明属于医药技术领域,具体涉及一种盐酸阿比多尔在制备改善或治疗肝损伤和肝纤维化药物中的应用。
背景技术
盐酸阿比多尔(Arbidol HCl,ARB,CAS号:131707-23-8)是一种苏联设计的小分子吲哚衍生物(专利号:PCT SU88/00272(1990)),用于预防和治疗流感和其他呼吸道病毒感染,在俄罗斯和中国等国家获得广泛认可,有较强的抗流感病毒和其他呼吸道病毒活性(Beliaev AL,et al.Vestn Ross Akad Med Nauk,1996)。盐酸阿比多尔除对流感病毒有抑制作用外,对其他病毒如新型冠状病毒亦被报道有较强的抑制作用(Blaising,J.,etal.Antiviral Res,2014)(Jingya Zhao,et al.J Thorac Dis.2023)。
肝纤维化是肝脏受到损伤时的一种修复过程,过度的肝纤维化最终导致肝硬化。肝纤维化过程中有众多细胞参与,其中肝星状细胞起主导作用,当肝损伤发生时肝星状细胞会活化成为肌成纤维细胞从而合成和分泌胶原蛋白。
至今为止,未有盐酸阿比多尔治疗肝损伤、肝纤维化的有关报道。通过盐酸阿比多尔已知的性质无法推断其是否具有治疗肝损伤、肝纤维化的作用。
发明内容
发明目的:本发明目的在于针对现有技术的不足,提供一种盐酸阿比多尔在制备改善或治疗肝损伤和肝纤维化药物中的应用。盐酸阿比多尔对小鼠肝损伤及纤维化疾病具有明显改善作用;并可抑制肝星状细胞活化及由此引起的纤维化疾病。因此,可以将盐酸阿比多尔用于制备改善或治疗肝损伤和肝纤维化药物。
本发明实验研究发现,在胆管结扎(bile duct ligation,BDL)诱导的小鼠肝损伤模型中,术后7天每日2次灌胃给予不同剂量的盐酸阿比多尔(10mg/kg或20mg/kg)可以显著性减轻BDL诱导的小鼠血清肝细胞损伤指标(血清AST与ALT酶活力水平)上升,改善BDL诱导的小鼠肝组织病理学改变(假小叶形成、胶原纤维增生等),并具有一定剂量依赖性;而且20mg/kg盐酸阿比多尔的疗效与阳性药熊去氧胆酸(UDCA,30mg/kg)的疗效相当。实验结果表明,盐酸阿比多尔具有改善肝损伤及纤维化疾病的效果。在TGF-β1诱导的小鼠肝星状细胞活化模型中,给药5μM盐酸阿比多尔显著抑制TGF-β1诱导的小鼠肝星状细胞产生α-SMA。实验结果表明,盐酸阿比多尔具有抑制肝星状细胞活化的作用。
技术方案:本发明的目的通过下述技术方案实现:
本发明提供了一种盐酸阿比多尔在制备改善或治疗肝损伤和肝纤维化药物中的应用。
所述盐酸阿比多尔可以作为唯一活性成分制备改善或治疗肝损伤和肝纤维化药物。
所述盐酸阿比多尔还可以与其它药物联合使用制备改善或治疗肝损伤和肝纤维化药物。
所述药物包括盐酸阿比多尔及药学上可接受的载体或辅料。
所述辅料包含抗氧剂、乳化剂、防腐剂、稀释剂、增溶剂、润湿剂、崩解剂、黏合剂或润滑剂中的一种或几种。
所述抗氧剂选自抗坏血酸、亚硫酸盐、亚硫酸氢盐、没食子酸及其脂类中的至少一种。
所述乳化剂选自吐温类、司盘类、甘油脂肪酸酯类、果胶、琼脂、海藻酸钠或二氧化硅中的至少一种。
所述防腐剂选自苯甲酸及其盐类、山梨酸及其盐类或尼泊金酯类中的至少一种。
所述稀释剂选自淀粉类、糖类、纤维素类或无机盐类中的至少一种。
所述增溶剂选择吐温类、聚氧乙烯脂肪醇醚类、硫酸化物或磺酸化物中的一种。
所述润湿剂选自水或乙醇中的至少一种。
所述崩解剂选自淀粉、羧甲基淀粉钠、交联聚维酮、低取代羟丙基纤维素或交联聚乙烯吡咯烷酮中的至少一种。
所述黏合剂选自淀粉浆、羧甲基纤维素钠、聚维酮、羟丙基纤维素、甲基纤维素或乙基纤维素中的至少一种。
所述润滑剂选自硬脂酸镁、滑石粉、氢化植物油、聚乙二醇类或微粉硅胶中的至少一种。
所述药物的剂型为颗粒剂、片剂、胶囊剂、混悬剂、口服液、注射剂或输液剂。在治疗各种原因所致肝损伤及纤维化疾病时,以盐酸阿比多尔为活性成分,以常规的制剂工艺,制备成在临床上可以使用的药物,如丸剂、片剂、胶囊剂和口服液剂等,能够通过抑制肝星状细胞活化,改善各种原因引起的肝损伤及纤维化疾病。
本发明的药物可以采用各种已知的方式施用,例如口服、注射、通过吸入喷雾施用。本发明的药物可单独给药也可与其他药物联合用药。口服组合物可以是任何口服可接受的剂型。无菌可注射组合物可按照本领域已知的技术,使用适合的分散剂或润湿剂和助悬剂来配制。可以使用的药学上可接受的载体和溶剂包括水、氯化钠溶液等。
本发明药物可以制成普通制剂,也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
可以改变本发明的药物中活性成分的实际剂量水平以获得对特定患者、组合物和施用方式而言可以有效实现所需治疗响应、对患者无毒的活性成分的量。所选择的剂量水平取决于多种因素,包括施用途径、施用时间、排泄速率、治疗的持续时间、与盐酸阿比多尔组合使用的其它药物、化合物和/或材料、所治疗的患者的年龄、性别、体重、一般健康状况和既往病史以及医学领域中公知的类似因素。
所述盐酸阿比多尔显著降低BDL小鼠血清AST与ALT酶活力水平。
所述盐酸阿比多尔改善BDL诱导的小鼠肝组织病理学改变。
给药5μM盐酸阿比多尔显著抑制TGF-β1诱导的小鼠肝星状细胞产生α-SMA。
20mg/kg盐酸阿比多尔的疗效与30mg/kg阳性药熊去氧胆酸UDCA的疗效相当。
有益效果:
本发明所述的盐酸阿比多尔可用作活性成分,应用于改善各种原因所致肝损伤及肝纤维化疾病的药物中,开拓了盐酸阿比多尔的新用途,为改善各种原因所致肝损伤及肝纤维化疾病的药物提供了新选择。盐酸阿比多尔对小鼠肝损伤及纤维化疾病具有明显改善作用;并可抑制肝星状细胞活化及由此引起的纤维化疾病。因此,盐酸阿比多尔能够用于制备改善或治疗肝损伤和肝纤维化疾病的药物,所述肝纤维化疾病包括但不限于急慢性肝炎、肝硬化、脂肪肝。
附图说明
图1为盐酸阿比多尔改善BDL诱导的小鼠肝损伤及纤维化的病理检查结果;
图2为盐酸阿比多尔抑制TGF-β1诱导的小鼠肝星状细胞活化。
具体实施方式
下面通过具体实施例对本发明技术方案进行详细说明,但是本发明的保护范围不局限于所述实施例。
实施例1胆管结扎(Bile duct ligation,BDL)诱导的小鼠肝损伤模型的建立
1、实验动物
购自济南朋悦实验动物繁育有限公司的36只SPF级的C57BL/6J雄性小鼠,8周龄,体重20-22g,实验前将小鼠放置在安静、避强光的环境中饲养一周以适应环境,光照与黑暗时间比为1:1,室温控制在22-25℃,湿度55%,小鼠能够自由进食和饮水。
2、实验材料
本实施例所用实验材料见表1:
表1实验材料
3、实验方法
(1)随机分组
取6只笼子用标记笔依次编号,动物临时编号为第一笼1~6号,第二笼7~12号,依次至第六笼31~36号,随意抓取小鼠称重,每笼放入6只,并用黑色记号笔按划1条横线为1、划2条横线为2,以此类推划6条横线为6的次序在小鼠的尾巴上临时记号。运用Excel软件将小鼠体重按从大到小排序,从统计学教科书中获取随机数字表,对动物进行重新分组。
将小鼠随机分为6组,即假手术组(Sham+Veh)、空白给药组(Sham+20mg/kg/dARB)、BDL组(BDL+Veh)、ARB低剂量组(BDL+10mg/kg/d ARB)、ARB高剂量组(BDL+20mg/kg/d ARB)以及阳性药UDCA组(BDL+30mg/kg/d UCDA)。
假手术组:只进行打开腹腔和皮肤缝合的操作,不进行胆管结扎,图1中用“Sham”表示。
BDL组:胆管结扎诱导的模型组,图1中用“BDL”表示。
Veh表示:纯水+3%吐温80+5%二甲基亚砜DMSO。
假手术组、BDL组均给予相同体积的Veh。
(2)建立BDL模型
手术前一天晚上禁食,将所有非无菌耗材121℃20min灭菌后烘干。实验开始前,打开小电热毯使温度保持在37℃以上,一个解剖皿倒入生理盐水,两个解剖皿倒入碘伏,将缝合线泡在倒满碘伏的解剖皿内,将结扎线剪成约5cm的若干段泡在另一个碘伏解剖皿内,将医用胶带也剪成约5cm的若干段备用。腹腔注射三溴乙醇溶液0.2mL/10g麻醉小鼠,用剃须刀片将小鼠胸腹部的毛刮净,用胶带固定四肢在硬纸板上,放在电热毯上。用棉棒在胸腹间涂满碘伏,依次剪开外皮内皮,从腹部往上剪到剑突附近,开口越小越好,用两个沾湿生理盐水的棉棒分别把肝和胃肠轻柔的往上和往下拨开,可以看到有一根和门静脉并行的透明细管即为胆总管。小心的分离开并行的血管,从胆总管下穿两根结扎线结扎两个结,从两个结中间剪断胆总管。将肝和胃肠恢复原来位置,依次缝合内外皮,缝合处涂满碘伏,腹部朝上放在铺了干净垫料的鼠笼里,放在取暖器附近等待小鼠苏醒,通常30min内应该醒来。造模时间为7天,造模前三天每天在小鼠伤口处涂一次碘伏。
实施例2盐酸阿比多尔改善BDL诱导的小鼠肝损伤实验
实验方法:
(1)给药与取材
将经过实施例1手术后的小鼠放置在与之前相同环境饲养7天。手术后第二天开始给药(按照实施例1中的分组给药),每日2次灌胃给药,所述灌胃的时间为每天的9点和21点(24小时制)。第8天摘眼球取血,室温放置30min后,3,000转离心15min,取上层血清-20℃冰箱保存。心脏灌流尽量冲去肝内的血液(肝脏变白),取下肝脏选较大的左外侧叶或中叶切去肝叶边缘,中间部分肝脏组织块放入4%多聚甲醛溶液中固定。
(2)血清ALT、AST水平检测
检测使用试剂盒采用的是赖氏法与微板法,按照试剂盒说明书(南京建成生物工程研究所有限公司,货号:C010-2-1/C009-2-1)要求进行实验,反应完成后用酶标仪(奥地利TECAN)检测510nm处吸光度值,按照说明书所给标准曲线进行换算得到酶活性水平。
(3)数据统计
所有数据采用Graphpad Prism 6软件进行统计,数据均以mean±SEM的形式表示,组别间显著性差异使用Student’s t检验;多组之间的显著性差异使用单因素方差分析及Boferroni后检验。P<0.05表示具有显著性差异。
实验结果:
小鼠BDL造模7天后,血清AST与ALT酶活力水平上升,与Sham+Veh组小鼠相比,具有显著性差异。为了确定盐酸阿比多尔是否能改善胆管结扎诱导的肝细胞损伤,在造模7天每天给予各组小鼠灌胃10mg/kg和20mg/kg剂量的盐酸阿比多尔后,检测血清AST与ALT酶活力水平。如表2所示,与BDL+Veh组相比,连续7天灌胃小鼠10mg/kg/d和20mg/kg/d剂量的盐酸阿比多尔以及30mg/kg/d剂量的UDCA显著降低BDL小鼠血清AST与ALT酶活力水平,表明肝细胞损伤减轻。
表2给药后各组小鼠血清AST与ALT酶活力水平的比较(Mean±SEM)
注:与Sham+Veh组比较,**P<0.01,与BDL+Veh组比较,#P<0.05,##P<0.01。
实施例3盐酸阿比多尔对小鼠肝组织病理情况的影响
实验方法:
(1)固定、脱水与透明
将实施例2中肝脏组织块投入预先配好的4%多聚甲醛固定液,常温固定2天。将组织放入75%、85%、95%、100%、100%的乙醇中脱水。将脱水好的组织放入两次纯二甲苯中进行透明。
(2)浸蜡与包埋
将置于二甲苯的组织放入40℃烘箱中烘烤40min,再放入两次新石蜡,每次0.5h。将已溶化的石蜡倒入先制备好容器,迅速夹取已浸透石蜡的组织块放入其中。冷却凝固成块。
(3)切片与贴片
将包埋好的蜡块固定于切片机(德国莱卡Leica)上切成5-8μm薄片,放入加热的水中烫平,再贴到载玻片上,放45℃恒温箱中烘干。
(4)H&E染色
染色前须用二甲苯脱去切片中的石蜡,再经由高浓度到低浓度酒精,最后入蒸馏水,然后进行染色。H&E染色使用苏木精(Hematoxylin,H)和伊红(Eosin,E)染料(弗瑞思生物),将已入蒸馏水后的切片放入苏木精水溶液中染色数分钟,然后于酸水及氨水中分色,自来水和蒸馏水洗净后入70%和90%酒精中脱水各10min,入酒精伊红染色液染色2-3min后重复上述脱水、透明步骤,最后树胶封片。
(5)Masson染色
石蜡切片先脱蜡至水,依次自来水和蒸馏水洗,用Regaud氏苏木精染液染核5-10min,充分水洗后用Masson丽春红酸性复红液(弗瑞思生物)5-10min,以2%冰醋酸水溶液浸洗片刻和1%磷钼酸水溶液分化3-5min,直接用苯胺蓝或光绿液染5min,以0.2%冰醋酸水溶液浸洗片刻,最后脱水、透明、封片。
(6)天狼星红(Sirius red)染色
石蜡切片先脱蜡至水,依次自来水和蒸馏水洗,Sirius red染色液(弗瑞思生物)处理1h,流水冲洗和0.5%醋酸浸洗片刻,最后脱水、透明、封片。
(7)扫描病理切片
使用中国药科大学大型仪器共享管理平台NanoZoomer 2.0RS切片扫描仪(日本滨松光子学株式会社),调整10×视野下扫描H&E染色、Masson染色和Sirius red染色病理切片。
(8)病理学评价
使用ImageJ软件的Color Threshold功能对Masson染色和Sirius red染色进行胶原面积统计,统计蓝色和红色的区域面积占比;H&E染色病理切片采用METAVIR评分系统进行肝组织纤维化分期评分(F0:无纤维化;F1:汇管区纤维性扩大,但无纤维间隔形成;F2:汇管区纤维性扩大,少数纤维间隔形成;F3:多数纤维间隔形成,无硬化结节;F4:肝硬化)。
(9)数据统计
所有数据采用Graphpad Prism 6软件进行统计,数据均以mean±SEM的形式表示,组别间显著性差异使用Student’s t检验;多组之间的显著性差异使用单因素方差分析及Boferroni后检验。P<0.05则有显著性差异。
实验结果:
如图1和表3所示,H&E染色病理切片可见BDL造模后小鼠肝小叶结构遭到破坏,各肝小叶间界限变得明显,假小叶形成,汇管区扩大并有大量增生的纤维结缔组织,甚至进一步在肝组织中形成胶原纤维增生,Masson染色和Sirius red染色胶原面积(Masson染色中染成蓝色的区域和Sirius red染色中染成红色的区域面积占比)显著增加,说明BDL手术成功诱导了小鼠肝纤维化发生。而给药UDCA和ARB后上述各情况得到明显改善,与BDL+Veh组相比,给药组H&E染色病理评分以及Masson染色和Sirius red染色病理切片的胶原面积占比显著下降,表明给药UDCA和ARB后肝纤维化程度显著减轻。
表3给药后各组小鼠肝组织病理学评价的比较(Mean±SEM)
注:与Sham+Veh组比较,**P<0.01,与BDL+Veh组比较,#P<0.05,##P<0.01。
实施例4盐酸阿比多尔抑制小鼠肝星状细胞活化
本实施例所用实验材料见表4:
表4实验材料
实验方法:
(1)配置培养基
培养基成分见表5:
表5培养基成分
灭活:57℃水浴30min
(2)原代小鼠肝星状细胞提取
所有操作均在超净台中进行。将灌流用的PBS和DMEM Low glucose配置的1mg/mL4型胶原酶(Collagenase Type 4)溶液42℃预热,4%水合氯醛麻醉小鼠(济南朋悦实验动物繁育有限公司,SPF级的C57BL/6J雄性小鼠,8周龄,体重20-22g),75%酒精消毒皮毛并固定四肢,将小鼠从腹部剪开到剑突打开腹腔,肠系膜中一根较粗的血管直通肝脏为肝门静脉,用镊子轻柔的将肝门静脉分出,将留置针插进血管并剪开腹部的下腔静脉,蠕动灌流PBS冲出污血,然后改成灌流1mg/mL 4型胶原酶溶液20mL后停止灌流。取下肝脏放在15mL 1mg/mL的4型胶原酶溶液中用镊子撕碎肝脏,尽量挑出筋膜,用无菌滴管将液体转移到50mL离心管内,加入DMEM Low glucose配置的1mg/mL DNA酶(Deoxyribonuclease 1)溶液300-400μL,37℃水浴锅中90次/min震荡消化20min。液体70μm细胞滤网过滤到一个新的50mL离心管内,600g离心10min弃上清。然后用DMEM Low glucose补到15mL,加150μL 1mg/mL DNA酶溶液,滴管吹打均匀,600g离心10min弃上清,然后重复上述操作1次。加2mL DMEM Low glucose到弃去上清的沉淀中,吹打混匀。将40% Percoll分离液(2.4mL的100% Percoll+1.6mL的生理盐水)缓缓延壁加入盛有60% Percoll分离液(1.6mL的100% Percoll+2.4mL的生理盐水)的15mL离心管内,将2mL细胞液缓缓延壁加进管内,将离心机的升速降速调为1和0,防止细胞停止震荡重悬,设置1,500g离心20min,吸取离心管刻度7.8-8.8mL处的细胞层,用DMEMLow glucose补到5mL,将离心机(Thermo Fisher Scientific)的升速降速调回9和7,600g离心10min,弃上清。若消化完全一只8周龄C57BL/6J雄鼠能分离得到HSC大约6×106个,加贴壁培养基吹打均匀,铺进96孔黑壁透底微孔板(Corning)。于培养箱内培养使HSC贴壁,2h后用PBS较轻力度吹打皿底两次,将不能贴壁的细胞洗掉,加入长期培养基培养。
(3)细胞培养和给药
将HSC铺入96孔黑壁底透板24h后,用含2%胎牛血清的饥饿培养基配制含10μM浓度的ARB、含相同浓度DMSO和含20ng/mL的TGF-β1的给药培养基,将培养培养基更换为含ARB的给药培养基或含相同浓度DMSO的给药培养基,放回细胞培养箱中继续培养1h进行预给药;然后每孔加入相同体积的含TGF-β1的给药培养基,使ARB终浓度为5μM,TGF-β1终浓度为10ng/mL,放回细胞培养箱中继续培养24h。
表6中Veh表示含2%胎牛血清的饥饿培养基配制的含相同浓度DMSO的给药培养基,在图2中用“DMSO”表示。
(4)固定、透化、封闭
给药结束后,将细胞用温热的PBS缓冲液清洗3次,再加入60μL/孔的含4%多聚甲醛的PBS缓冲液固定细胞,室温条件下固定30min。固定结束后,吸弃多聚甲醛溶液,往细胞外液中加入60μL/孔的含0.15% Triton X-100的PBS缓冲液,室温条件下透化10min。透化结束后,吸弃Triton X-100溶液,往细胞外液中加入60μL/孔的含5% BSA的PBS缓冲液,室温条件下封闭1h。
(5)孵育抗体
封闭结束后吸弃BSA溶液,按照说明书比例(1:300)用上述BSA溶液配置α-SmoothMuscle Actin(D4K9N)Rabbit mAb溶液,每孔加入50μL,4℃孵育过夜。孵育结束后,回收抗体,用BSA溶液清洗细胞3次,按照说明书比例(1:1,000)用上述BSA溶液配置Anti-rabbit IgG(H+L),F(ab')2Fragment(Alexa Fluor 488Conjugate)溶液,每孔加入50μL,室温条件下避光孵育1h。
(6)孵育Hoechst 33342
孵育抗体结束后,吸弃抗体,用PBS缓冲液清洗细胞3次,加入Hoechst 33342染液染细胞核,室温条件下避光孵育20min,孵育结束后PBS缓冲液清洗细胞3次。
(7)拍摄与统计
使用Leica Microsystems CMS GmbH Ernst-Leitz-Str显微镜(德国莱卡Leica)和附带的Application Suite X(LAS X)软件进行荧光拍摄。拍摄绿色荧光使用FITC滤光片,拍摄蓝色荧光使用DAPI滤光片。视野总细胞核个数的统计使用ImageJ软件,人工统计被绿色荧光覆盖的α-SMA阳性细胞个数,α-SMA阳性细胞数/视野总细胞核个数得到肝星状细胞活化比例。
(8)数据统计
所有数据采用Graphpad Prism 6软件进行统计,数据均以mean±SEM的形式表示,组别间显著性差异使用Student’s t检验;多组之间的显著性差异使用单因素方差分析及Boferroni后检验。P<0.05则有显著性差异。
实验结果:
在荧光显微镜下观察,各组原代小鼠肝星状细胞核呈蓝色,圆形,无细胞核固缩的情况(图2第一列Hoechst 33342染色图片);α-SMA呈现绿色荧光,均匀分布在小鼠肝星状细胞质中(图2第二列α-SMA染色图片),但具有α-SMA荧光信号的细胞数量在各组之间有差异(图2第三列MERGE染色图片,由第一列图片和第二列图片重叠而成)。如图2和表6所示,与DMSO组(Veh)相比,TGF-β1(TGF-β1+Veh)刺激使小鼠肝星状细胞α-SMA阳性细胞比例显著上升(P<0.01),说明TGF-β1刺激能使小鼠肝星状细胞显著活化。给药5μM盐酸阿比多尔(Veh+ARB)与DMSO组(Veh)相比小鼠肝星状细胞α-SMA阳性细胞比例无显著性差异。而TGF-β1刺激同时给药5μM盐酸阿比多尔(TGF-β1+ARB)与TGF-β1刺激组(TGF-β1+Veh)相比小鼠肝星状细胞α-SMA阳性细胞比例显著下降(P<0.01),这表明盐酸阿比多尔可抑制TGF-β1诱导的小鼠肝星状细胞活化。
表6给药后各组小鼠肝星状细胞α-SMA阳性细胞比例的比较(Mean±SEM)
注:与Veh组(DMSO组)比较,**P<0.01,与TGF-β1+Veh组比较,##P<0.01。
如上所述,尽管参照特定的优选实施例已经表示和表述了本发明,但其不得解释为对本发明自身的限制。在不脱离所附权利要求定义的本发明的精神和范围前提下,可对其在形式上和细节上作出各种变化。
Claims (10)
1.盐酸阿比多尔在制备改善或治疗肝损伤和肝纤维化药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述盐酸阿比多尔作为唯一活性成分制备改善或治疗肝损伤和肝纤维化药物。
3.根据权利要求1所述的应用,其特征在于,所述盐酸阿比多尔与其它药物联合使用制备改善或治疗肝损伤和肝纤维化药物。
4.根据权利要求1所述的应用,其特征在于,所述药物包括盐酸阿比多尔及药学上可接受的载体或辅料。
5.根据权利要求4所述的应用,其特征在于,所述辅料包含抗氧剂、乳化剂、防腐剂、稀释剂、增溶剂、润湿剂、崩解剂、黏合剂或润滑剂中的一种或几种。
6.根据权利要求1所述的应用,其特征在于,所述药物的剂型为颗粒剂、片剂、丸剂、胶囊剂、混悬剂、口服液、注射剂或输液剂。
7.根据权利要求1所述的应用,其特征在于,所述盐酸阿比多尔显著降低BDL小鼠血清AST与ALT酶活力水平。
8.根据权利要求1所述的应用,其特征在于,所述盐酸阿比多尔改善BDL诱导的小鼠肝组织病理学改变。
9.根据权利要求1所述的应用,其特征在于,给药5μM盐酸阿比多尔显著抑制TGF-β1诱导的小鼠肝星状细胞产生α-SMA。
10.根据权利要求1所述的应用,其特征在于,20mg/kg盐酸阿比多尔的疗效与30mg/kg阳性药熊去氧胆酸UDCA的疗效相当。
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HAILONG LI 等: "Protective Effect of Arbidol Against Pulmonary Fibrosis and Sepsis in Mice", 《FRONT. PHARMACOL.》, vol. 11, 27 January 2021 (2021-01-27), pages 1 - 8 * |
范婷婷: "肝细胞核因子4α治疗大鼠实验性肝硬化", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》, no. 9, 15 September 2011 (2011-09-15), pages 064 - 27 * |
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